Isothiocyanate derivatives of 9-[3-(cis-3,5-dimethyl-1- piperazinyl)propyl]-carbazole (rimcazole): Irreversible ligands for the dopamine transporter

Stephen M. Husbands, Sari E Izenwasser, Richard J. Loeloff, Jonathan L. Katz, Wayne D. Bowen, Bertold J. Vilner, Amy Hauck Newman

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Cocaine has been reported to bind to the dopamine transporter in a biphasic fashion, and it has been hypothesized that the low-affinity component may play a modulatory role in cocaine's psychomotor stimulant effects. In an effort to gain further insight into the roles of the two sites, we have prepared a series of irreversible ligands based on rimcazole (9-[3-(cis-3,5-dimethyl-1-piperazinyl)propyl]carbazole, 2), a compound that has been postulated to bind only to the low-affinity site. The alkylating moiety (isothiocyanate) is attached to the distal nitrogen of the piperazine ring via alkyl chains of varying lengths or directly attached to one of the aromatic groups. It was found that substitution on the piperazine nitrogen caused an initial decrease in affinity that was recovered as the alkyl chain length increased. Importantly, the analogue 16, with the highest affinity for the dopamine transporter (DAT), binds in a monophasic and irreversible manner, as evidenced by the greatly diminished binding of [3H]WIN 35,428 in tissue that had been preincubated with the ligand and then thoroughly washed using centrifugation. The dose-dependent reduction in B(max) was accompanied by a concentration-related decrease in KD values. This shift in K(D) to a lower value suggests that the preincubation with 16 produced a preferential irreversible binding to the low-affinity [3H]WIN 35,428 site on the dopamine transporter. These ligands may prove to be important tools with which to study the significance of the low-affinity site on the DAT. Since rimcazole does not share the behavioral profile of cocaine, and in fact appears to play a modulatory role, these compounds may provide leads for a novel cocaine- abuse treatment.

Original languageEnglish
Pages (from-to)4340-4346
Number of pages7
JournalJournal of Medicinal Chemistry
Volume40
Issue number26
DOIs
StatePublished - Dec 1 1997
Externally publishedYes

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Dopamine Plasma Membrane Transport Proteins
Cocaine
Ligands
Derivatives
Nitrogen
Cocaine-Related Disorders
Centrifugation
Chain length
Substitution reactions
Tissue
rimcazole
carbazole
isothiocyanic acid
piperazine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Isothiocyanate derivatives of 9-[3-(cis-3,5-dimethyl-1- piperazinyl)propyl]-carbazole (rimcazole) : Irreversible ligands for the dopamine transporter. / Husbands, Stephen M.; Izenwasser, Sari E; Loeloff, Richard J.; Katz, Jonathan L.; Bowen, Wayne D.; Vilner, Bertold J.; Newman, Amy Hauck.

In: Journal of Medicinal Chemistry, Vol. 40, No. 26, 01.12.1997, p. 4340-4346.

Research output: Contribution to journalArticle

Husbands, Stephen M. ; Izenwasser, Sari E ; Loeloff, Richard J. ; Katz, Jonathan L. ; Bowen, Wayne D. ; Vilner, Bertold J. ; Newman, Amy Hauck. / Isothiocyanate derivatives of 9-[3-(cis-3,5-dimethyl-1- piperazinyl)propyl]-carbazole (rimcazole) : Irreversible ligands for the dopamine transporter. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 26. pp. 4340-4346.
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abstract = "Cocaine has been reported to bind to the dopamine transporter in a biphasic fashion, and it has been hypothesized that the low-affinity component may play a modulatory role in cocaine's psychomotor stimulant effects. In an effort to gain further insight into the roles of the two sites, we have prepared a series of irreversible ligands based on rimcazole (9-[3-(cis-3,5-dimethyl-1-piperazinyl)propyl]carbazole, 2), a compound that has been postulated to bind only to the low-affinity site. The alkylating moiety (isothiocyanate) is attached to the distal nitrogen of the piperazine ring via alkyl chains of varying lengths or directly attached to one of the aromatic groups. It was found that substitution on the piperazine nitrogen caused an initial decrease in affinity that was recovered as the alkyl chain length increased. Importantly, the analogue 16, with the highest affinity for the dopamine transporter (DAT), binds in a monophasic and irreversible manner, as evidenced by the greatly diminished binding of [3H]WIN 35,428 in tissue that had been preincubated with the ligand and then thoroughly washed using centrifugation. The dose-dependent reduction in B(max) was accompanied by a concentration-related decrease in KD values. This shift in K(D) to a lower value suggests that the preincubation with 16 produced a preferential irreversible binding to the low-affinity [3H]WIN 35,428 site on the dopamine transporter. These ligands may prove to be important tools with which to study the significance of the low-affinity site on the DAT. Since rimcazole does not share the behavioral profile of cocaine, and in fact appears to play a modulatory role, these compounds may provide leads for a novel cocaine- abuse treatment.",
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